Age is associated with changes in the brain environment which predispose towards neurodegenerative[unreadable] disease. One contributing element to the brain environment is the brain's resident monocytic cells, the[unreadable] microglia. Activation of microglia can result in release of inflammatory factors. The general perception was[unreadable] that more microglial activation would cause greater release of inflammatory mediators, which would[unreadable] contribute to more neurodegeneration in Alzheimer's disease, Parkinsons's disease and stroke. However,[unreadable] studies in several laboratories now indicate that some forms of microglial activation can benefit[unreadable] neurodegenerative disease. Studies of peripheral macrophages have led to identification of several distinct[unreadable] activation states, referred to variously as M1 and M2 or classical and alternative. These are characterized by[unreadable] different markers being expressed and different functions of the cells. To date, distinct activation states of[unreadable] microglia in brain have not been well characterized. In aim 1 we will test the ability of M1 specific and M2[unreadable] specific microglial activation cocktails to induce expression of multiple markers, some general and some[unreadable] specific to each activation state. It is anticipated that the magnitude and duration of responses to these[unreadable] agents will be altered with aging, with old mice having a greater propensity towards an M1 proinflammatory[unreadable] activation state. A second aim will investigate whether changes in the brain environment regulate the amount[unreadable] of histopathology present. For example, in APP transgenic mouse models of amyloid deposition/the amount[unreadable] of Abeta deposited in brain increases with age. But, it is knot known whether this occurs because of the[unreadable] passage of time, or whether the age of mouse is playing a critical role in the amount of Abeta deposited. We will[unreadable] examine this by suppressing Abeta deposition for 6 mo in two different mouse models and then releasing it from[unreadable] suppression. If the Abeta deposition accumulates at a similar but delayed rate, time will be viewed as the critical[unreadable] factor. However, if the Abeta deposition reaches the same level in both conditions several months after the[unreadable] release from suppression, then clearly the aged brain environment is playing a critical role. Finally, in[unreadable] collaboration with other projects in the program, we will investigate whether increases in microglial activation[unreadable] caused by depletion of noradrenaline, or decreases in microglial activation associated with LFA-1 null[unreadable] condition modify the extent of amyloid deposition and memory loss in APP transgenic mice.